This weekly seminar aims at gathering researcher form different thematics (physicists, biologists and chemists) and from different institutes in the center of Paris. The objective is to cover an interface between physics, chemistry and biology as broad as possible, with experimental, numerical and/or theoretical approaches. To describe life sciences all scales are needed, from single molecules, cell biology, organisms, population dynamics. That's why the range of our seminar is quite broad form embryonic development, genetic regulation, evolution, mechanics and cell migration, immunology, microbiology, synthetic biology, etc.
21 May 2021, 1pm - Peter Swain (University of Edinburgh)
During chemical navigation organisms must detect molecules, process that information, and make decision (e.g. turn or not to turn), which affects the signal they will encounter next. I will report on recent experiments in our lab that examine different aspects of this process. In the first part of the talk, I will discuss experiments that quantified the strategy used by walking fruit flies to navigate complex odor plumes, when the location and timing of odor packets are uncertain. In the second part of the talk, I will use the simpler and better characterized E. coli chemotaxis system to quantify how information puts a bound on maximal navigational performance, and how efficient a bacterium is at using the information it gathers in order to navigate.
Podosomes are macrophage adhesion structures devoted to the proteolysis of the extracellular matrix that are constitutively formed by monocyte/macrophage-derived cells. We have shown that they are crucial for the capability of macrophages to perform macrophage protease-dependent mesenchymal migration in vivo. Therefore, podosomes are emerging as specific targets to limit the deleterious macrophage infiltration in tumors. Podosomes are composed of a core of F-actin surrounded by adhesion complexes. We have shown that podosomes are capable of applying protrusive forces onto the extracellular environment, thanks to the development of a method called Protrusion Force Microscopy, which consists in measuring by Atomic Force Microscopy the nanometer deformations produced by macrophage podosomes on a compliant formvar membrane. We estimated the protrusive force generated at podosomes and showed that it oscillates with a constant period and requires combined acto-myosin contraction and actin polymerization. We have demonstrated that talin, vinculin and paxillin sustain protrusion force generated at the podosome core, and related force generation to the molecular extension of talin within the podosome ring, indicating that the ring sustains mechanical tension. We are now investigating the organization and regulation of actin filaments in podosomes and the precise localization of actin cross-linkers. Next to the demonstration that the ring is a site of tension balancing protrusion at the core, we are now determining how actin filaments in the core are collectively organized to generate podosome protrusive forces. Using in situ cryo-electron tomography, we have recently unveiled how the nanoscale architecture of macrophage podosomes enables basal membrane protrusion. In particular, we could show that the sum of the actin polymerization forces at the membrane is not sufficient to explain podosome protrusive forces, but that it can be rather explained by the elastic energy that is accumulated inside podosome actin filaments.
The spin glass is a paradigmatic example of a difficult optimization problem arising from simple pairwise interactions, and unsurprisingly recurs in many contexts. One such context is the study of evolution, where spin-glass-like models are extensively used to simulate the complex "fitness landscape" experienced by the organisms as they evolve and interact. I will describe a class of eco-evolutionary models focusing on the simplest case of the interaction between organisms and their environment, namely competition for limited resources. In this class of models, the glassy landscape acquires the meaning of specifying the (complex, idiosyncratic) biochemistry. Focusing on the ecosystem response to external perturbations, I will argue that the spin-glass intuition allows us to expect several parameter regimes with distinct behaviors. In particular, the intuitive regime ("what the community is doing depends on the species it contains") is flanked by two regimes where ecosystem response is predictable: one where this predictability emerges in spite of biochemical details, and another where it arises because of them.
Specific cell and tissue form is essential to support many biological functions of living organisms. During development, the creation of different shapes fundamentally requires the integration of genetic, biochemical and physical inputs.
In plants, it is well established that the cytoskeletal microtubule network plays a key role in the morphogenesis of the plant cell wall by guiding the organisation of new cell wall material. The cell cytoskeleton is thus a major determinant of plant cell shape. What is less clear is how cell geometry in turn influences the cytoskeletal organization.
To explore the relative contribution of geometry to the final organization of actin and microtubule cytoskeletons in single plant cells, we developed an experimental approach combining confinement of plant cells into micro-niches of controlled geometry with imaging of the cytoskeleton. A model of self-organizing microtubules in 3D predicts that severing of microtubules is an important parameter controlling the anisotropy of the microtubules network. We experimentally confirmed the model predictions by analysis of the response to shape change in plant cells with altered microtubule severing dynamics. This work is a first step towards assessing quantitatively how cell geometry controls cytoskeletal organization in plants.
Cells in growing tissues are continuously subjected to and exerting active and passive forces. In fact, growth rate variations or changes in the spatial orientation of growth produce stress. To release the produced stress, the balance between growth and cell division is fundamental. Here we investigate the consequences on cell morphology when this balance is not present. A perfect model system is Drosophila abdominal epidermis, a continuous cell layer formed of two cell types: larval epithelial cells (LECs), and adult epidermis precursors (histoblasts). Histoblasts are organized in nests surrounded by LECs. Interestingly, histoblasts grow without dividing throughout the whole larval life. At the same time, LECs grow at a faster rate than histoblasts. Such imbalance causes an amazing morphological change in histoblasts, with cell junctions changing from straight to deeply folded. Such transition is reminiscent of buckling instabilities. We hypothesize that growing LECs compress histoblasts, causing junctional buckling. Live imaging observations of larvae in which we genetically altered cell cycle or growth of either cell type support this idea. Hence, we show that altering the balance between cell growth and divisions leads to unexpected morphological and mechanical regimes.
Cell migration and cell mechanics play a crucial role in a number of key
biological processes, such as embryo development or cancer metastasis.
It is therefore important to characterise the material properties of
cells and tissues and the way they mechanically interact with their
In this talk, I will present recent work we did to address these questions at the single-cell and tissue level. In particular, experimental studies on the mechanical response of in-vitro epithelial monolayers show that the material exhibits a strong time-dependent response over a broad range of timescales. In this situation, it is challenging to capture the response of the system with a few parameters without losing some of the material’s characteristic features. I will show that rheological models based on fractional calculus are effective empirical tools to summarize such complex data and highlight similarities across a broad range of systems.
Left-right partitioning of the heart underlies the double blood circulation : pulmonary circulation in the right heart, systemic circulation in the left heart. Asymmetric heart morphogenesis is initiated in the embryo, when the tubular primordium acquires a rightward helical shape during the process of heart looping. This shape change determines cardiac chamber alignment and thus heart partitioning. Impairment of the left-right patterning of mesoderm precursor cells leads to the severe heterotaxy syndrome, including complex cardiac malformations and failure to establish the double blood circulation. Whereas the molecular cascade breaking the symmetry has been well characterised, how asymmetric signalling is sensed by precursor cells to generate asymmetric organogenesis has remained largely unknown.
Heart looping had been previously analysed as a binary parameter (left/right) of the helix direction, taken as a readout of the symmetry-breaking event. However, this is too reductionist to describe a 3D shape. We have developed a novel framework to quantify and simulate the fine heart loop shape in the mouse, as a readout of asymmetric morphogenesis. This has led us to propose a model of heart looping centred on the buckling of the tube growing between fixed poles. We have re-analysed the role of the major left determinant Nodal in this context. We have traced the contribution of Nodal expressing cells to regions of the heart tube poles. By manipulating Nodal signalling in time and space, we show that it is not involved in the buckling, but that it biases it. Nodal is required transiently in heart precursors, to amplify and coordinate opposed asymmetries at the heart tube poles and thus generate a robust helical shape.
Ongoing work aims at further dissecting the dynamics of left-right patterning, beyond Nodal signaling. Thus, we provide novel insight into the mechanisms of asymmetric heart morphogenesis relevant to complex congenital heart defects.
Microorganismal motility is often characterised by complex responses to environmental physico-chemical stimuli. Although the biological basis of these responses is often not well understood, their exploitation already promises novel avenues to directly control the motion of living active matter at both the individual and collective level. Here we leverage the phototactic ability of the model microalga Chlamydomonas reinhardtii to precisely control the timing and position of localised cell photo-accumulation, leading to the controlled development of isolated bioconvective plumes. This novel form of photo-bio-convection allows a precise, fast and reconfigurable control of the spatio-temporal dynamics of the instability and the ensuing global recirculation, which can be activated and stopped in real time. A simple continuum model accounts for the phototactic response of the suspension and demonstrates how the spatio-temporal dynamics of the illumination field can be used as a simple external switch to produce efficient bio-mixing.
The olfactory system senses chemicals in the environment to guide behavior in animals. Fluctuating mixtures of chemicals, transported in fluid environments, are detected by an array of olfactory sensors and parsed by neural circuits to recognize odor objects, which then inform behavioral decisions. Some key questions for chemical sensing systems include how they can detect relevant molecules that are embedded in a sea of distractors, and how they use sparse intermittent stimuli to navigate. We work with theorists to frame these questions quantitatively and use experiments in mice to address them. I will present some examples from our recent and ongoing work.
Ageing is a complex process, broadly affecting living organisms in
extremely various ways, ranging from the negligible senescence of some
trees and arthropods, through the sudden post-reproduction death of
salmon and desert organisms, to our human ageing with what has long been
described as a time dependent exponential increase of the mortality risk.
Drosophila melanogaster and Mus musculus, the fruit fly and mouse, are two broadly used model organisms for studying ageing mostly because they show an apparent exponential increase of their mortality risk, same as in humans. Using the first model system, about 10 years ago I identified a physiological marker preceding death - fruit flies would turn blue when fed a non-toxic food dye. This simple visual cue allows us to identify individuals at a different stage of their life amongst a cohort of individuals and study aging and progress towards death.
We use this tool to question our knowledge regarding ageing, showed the broad conservation of this end-of-life phenotype in different drosophila subspecies, nematodes, zebrafish and killifish as well as develop a novel mathematical model for ageing allowing the experimental quantification of various "ageing parameters".
The cerebrospinal fluid (CSF) is a complex solution circulating around the brain and spinal cord. Multiple evidence indicate that the activity and the development of the nervous system can be influenced by the content and flow of the CSF. Yet, it is not known how neuronal activity changes as a function of the physico-chemical properties of the CSF.
We identify throughout vertebrate species, ciliated neurons at the interface between the CSF and the nervous system that are in ideal position to sense CSF cues, to relay information to local networks and to regulate CSF content by secretion.
By combining electrophysiology, optogenetics and calcium imaging in vivo in larval zebrafish, we demonstrate that neurons contacting the CSF detect local bending of the spinal cord and in turn feedback GABAergic inhibition to multiple interneurons driving locomotion and posture in the spinal cord and hindbrain. Such inhibitory feedback modulates neuronal target in a state-dependent manner, depending on the fact that the animal is at rest or actively moving at a define speed.
Behavioral analysis of animals deprived of this sensory pathway reveals differential effects on speed for slow and fast regimes, as well as impairments in the control of posture during active locomotion. Our work first sheds light on the cellular and network mechanisms enabling sensorimotor integration of mechanical and chemical cues from the CSF onto motor circuits controlling locomotion and posture in the spinal cord.
We will present converging evidence that this interoceptive sensory pathway is involved in guiding a straight body axis throughout life, as well as innate immunity via the detection and combat of pathogens intruding the CSF.
Epithelial monolayers are soft thin sheets which shape the body and organs of many multi-cellular organisms. Competition between stretching and bending characterizes shape transitions of thin elastic sheets. While stretching dominates the mechanical response in tension, bending dominates in compression after an abrupt buckling transition. As opposed to inert materials, the morphogenesis of epithelial monolayers is largely influenced by endogenous ATP-dependent forces, which generate in-plane tension and active torques due to the polarization of myosin II molecular motors.
Here, we address the dialog between in-plane and out-of-plane forces in vitro, in epithelial monolayers devoid of substrate and suspended between parallel plates.
I will show that curls of high curvature form spontaneously at the free edge of these monolayers, which we use to estimate the active torques and the bending modulus of the tissue. I will also show that these tissues buckle in response to compression in a time-dependent and myosin II-dependent manner.
Body and caudal fin undulations are a widespread locomotion strategy in fish, and their swimming kinematics is usually described by a characteristic frequency and amplitude of the tail-beat oscillation. In some cases, fish use intermittent gaits, where a single frequency is not enough to fully describe their kinematics. Energy efficiency arguments have been invoked in the literature to explain this so-called burst-and-coast regime but well controlled experimental data are scarce. I will discuss our recent results on an experiment with burst-and-coast swimmers and a numerical model based on the observations showing that the observed burst-and-coast regime can be understood as obeying a
minimization of cost of transport.
Ref: Li et al. (2020) Burst-and-coast swimmers optimize gait by adapting unique intrinsic cycle arXiv:2002.09176
Behavior exhibits multiple spatio-temporal scales: from fast control of the body posture by neural activity, to the slower neuromodulation of exploratory strategies all the way to ageing. How can we bridge these scales? We leverage the interplay between microscopic variability and macroscopic order, fundamental to statistics physics, to extract predictive coarse-grained dynamics from data. We reconstruct the state space as a sequence of measurements, partition the resulting space as to maximize entropy, and choose the sequence length to maximize predictive information. We approximate the dynamics of densities in the partitioned state space through transfer operators, providing an accurate statistical model on multiple scales. The operator spectrum provides a principled means of timescale separation and coarse-graining. We illustrate our approach using high-resolution posture measurements of the nematode C. elegans, and show that long-time changes in exploratory strategies (10's of minutes) can be extracted from fine scale posture samples (10's of milliseconds).
Metabolism and evolution are closely connected: if a mutation incurs extra energetic costs for an organism, there is a baseline selective disadvantage that may or may not be compensated for by other adaptive effects. A long-standing, but to date unproven, hypothesis  is that this disadvantage is equal to the fractional cost relative to the total resting metabolic expenditure. I will present our recent work  which validates this hypothesis from physical principles through a general growth model and show that it holds to excellent approximation for experimental parameters drawn from a wide range of species.
We will also overview the significance of this contribution from metabolic expenditures in the course of evolution, by considering the elements of population dynamics. As an example, I will demonstrate that a close inspection on the thermodynamic costs, noise suppression performance and selection shows intriguing aspects about the evolution of microRNA regulated gene networks which play a critical role by controlling developmental processes of complex organisms and related diseases.
 L. E. Orgel and F. H. Crick, Nature 284, 604 (1980)
 E. Ilker and M. Hinczewski, Phys. Rev. Lett. 122, 238101 (2019)
T cells have to make life-or-death immune decisions based on sensitive and specific interactions with self and/or foreign peptides. On a longer time scale, T cells have to coordinate with one another to trigger a properly balanced immune response. Modeling this process is a daunting task because of the multiplicity of molecular and cellular interactions. I will show how phenotypic models can be built to describe those processes in a simple and predictive way. At the single cell level, we propose an « adaptive kinetic proofreading » model, detecting ligand strength irrespective of ligand concentrations. This model predicts experimental features such as ligand antagonism, which, interestingly, can be related to adversarial problems in artificial neural networks. At the cell population level, I will introduce a data driven approach to build phenomenological models of collective response, suggesting the existence of a simple cytokine code.
Persistent neural activities are ubiquitous in neural systems. This capacity of networks to continuously discharge in the absence of on-going stimuli is believed to subserve short-term memorisation and temporal integration of sensory signals. Although persistence may reflect cellular mechanisms, it can also be a network emergent property. Here we investigate this latter mechanism on larval zebrafish, a model vertebrate that is accessible to brain-scale neuronal recording and high-throughput behavioral studies.
We thus combine behavioral assays, functional imaging and network modeling to understand the dynamics and function of a small bilaterally distributed neural circuit (ARTR). ARTR exhibits slow antiphasic alternations between its left and right subpopulation. This oscillation drives the coordinated orientation of the eyes and swim bouts, thus organizing the fish spatial exploration. The left/right transition can be induced through transient illumination of one eye such as to orient the fish towards towards light sources (phototaxis). We also show that the self-oscillatory frequency can be modulated by the water temperature. To elucidate the mechanism leading to the slow self-oscillation, we train a network (Ising) model on the neural recordings. The model allows us to generate synthetic oscillatory activity, whose features correctly captures the observed dynamics. It provides a simple physical interpretation of the persistent process.
We exploit a theoretical relation between two statistics on lineages trees,
based either on forward lineages or on backward histories [1,2]. A fitness landscape
is introduced, which quantifies the correlations between a trait of interest and
the number of divisions. We derive various inequalities constraining the
fluctuations of a trait of interest or its fitness on lineage trees.
We apply this formalism to single-cell experiments with bacteria populations,
carried out either in the mother machine configuration or in free conditions
using time-lapse video-microscopy. We also investigate how the various sources
of stochasticity at the single cell level can affect the population growth rate.
 Linking lineage and population observables in biological branching processes, R. Garcia-Garcia, A. Genthon and D. Lacoste, Phys. Rev. E, 042413 (2019).
 Fluctuation relations and fitness landscapes of growing cell populations, Scientific Reports, 10, 11889 (2020).
Ants exhibit some of the most diverse and complex patterns of collective behavior in nature. However, the systematic study of these patterns and their computational significance has long been hindered by the lack of a lab model system, which would allow precise manipulations of the determinants of these emergent patterns. In this talk, I will present the potential of a specific ant species, the clonal raider ant Ooceraea biroi, to become such a model system. I will briefly describe the unique properties of the species and the opportunities they open for the understanding of collective behavior. I will then present results from two separate projects, studying different aspects of collective behavior. In the first, we study how ant colonies respond collectively to sensory input. We show that their response is characterized by an emergent threshold, which is sensitive to manipulations of colony properties. I will discuss the implications of this emergence for the understanding of how ants use interactions to reach collective decisions. In the second study, we analyze a more ecologically relevant behavior, the group raid, which is a swift offensive response of a colony to the detection of a potential prey by a scout. I will highlight the differences between this behavior and a behavior exhibited by related ant species, the army ants. Based on these analyses, we suggest that the emergent differences between the two behaviors can be explained by evolutionary changes in colony size alone.
The concept of the hematopoietic stem cell developed from the observation, reported in the 1950s, that the transplantation of bone marrow from adult mice rescues irradiated mice by regenerating their blood. Transplantation experiments have been the mainstay of hematopoiesis research until recently, when non-invasive genetic tools for tracing the progeny of hematopoietic stem cells were developed. Based on these tools, we and others found that post-transplantation recovery differs fundamentally from physiological hematopoiesis. Mathematical models of cell population dynamics, coupled with statistical inference, have been playing a key role in deriving quantitative insights on stem cell behavior from experimental data and in designing new experiments. I will discuss recent work on how the murine hematopoietic system develops in the fetus and functions in the adult. We find that the stem cells, while being highly productive during development, are remarkably unproductive in the adult, even during times of high demand for blood and immune cells. Cell population genetics suggest a function for idle hematopoietic stem cells.
The extensive heterogeneity of biological data poses challenges to analysis and interpretation. Construction of a large-scale mechanistic model of Escherichia coli enabled us to integrate and cross-evaluate a massive, heterogeneous dataset based on measurements reported by various labs over decades. We identified inconsistencies with functional consequences across the data, including: that the data describing total output of the ribosomes and RNA polymerases is not sufficient for a cell to reproduce measured doubling times; that measured metabolic parameters are neither fully compatible with each other nor with overall growth; that essential proteins are absent during the cell cycle - and the cell is robust to this absence. Finally, considering these data as a whole leads to successful predictions of new experimental outcomes, in this case protein half-lives.
Equilibrium statistical mechanics tells us how to control the self-assembly of passive materials by tuning the competition between energy and entropy to achieve desired states of organization. Out of equilibrium, no such principles apply and self-organization principles are scarce. In this talk I will review the progress which has been made over the past ten years to control the organization of self-propelled agents using motility control, either externally or through interactions. I will show that generic principles apply and illustrate the theoretical developments presented in the talk using recent experiments on run-and-tumble bacteria.
We study the origin and function of signaling oscillations in embryonic development. Oscillatory activities (period ~2 hours) of the Notch, Wnt and Fgf signaling pathway have been identified in mouse embryos and are linked to periodic mesoderm segmentation and the formation of pre-vertebrae, somites. Most strikingly, Notch signaling oscillations occur highly synchronized, yet phase-shifted, in cell ensembles, leading to spatio-temporal wave patterns sweeping through the embryo. I will discuss how we use general synchronisation principles based on entrainment/Arnold tongues to reveal general properties and function of collective oscillations during the mesoderm patterning process.
Active fluids consist of self-propelled particles (as bacteria or artificial microswimmers) and display properties that differ strongly from their passive